Hydrazide fixed to a resin and derivatives thereof, and a method for synthesizing pyrazolones in solid phase

ABSTRACT

Hydrazide fixed to a resin represented by the following formula: 
     
       
         P—Q—CO—NH—NH 2   (I)  
       
     
     where P represents a main chain of a resin polymer and Q represents a hydrocarbon side chain optionally having a substituent which may be bonded via a heteroatom, and a hydrazone derived therefrom and fixed to a resin 
     
       
         P—Q—CO—NH—N═CH—R 1   (II)  
       
     
     are provided, and solid phase synthesis of pyrazolone is conducted using the same, thereby enabling synthesis of pyrazolones by the application of the Mannich type reaction based on the solid phase synthesis and efficient construction of libraries for various kinds of them.

This application is a 371 of PCT/JP99/01222 filed Mar. 12, 1999.

1. Field of the Invention

This invention concerns a hydrazide fixed to a resin and derivativesthereof, and a method for synthesizing pyrazolones in a solid phase.

2. Related Art Statement

Solid phase synthesis methods using a resin carrier have been known sofar in, for example, peptide synthesis, and the solid phase synthesismethod is an effective means for synthesizing a plurality kinds ofanalogous group of compounds all at once, and it has been considered toapply the solid phase synthesis method also to various kinds of chemicalreactions.

However, it has actually been a problem that reactions to which themethod is applicable are restricted in the solid phase reaction comparedwith liquid phase reaction which is predominant in the chemicalsynthesis. In view of the prior art situation described above for thesolid phase synthesis method, the inventors of the present applicationhave studied for improving the effectiveness of the solid phasesynthesis method by conducting carbon-carbon bond forming reactionswhich are most basic and important in the synthesis of organic compoundsefficiently on a solid phase.

In particular, the inventors of the present application have found anovel method of conducting a Mannich type reaction starting from an acylhydrazone using a catalyst and it is an important subject to establish asolid phase synthesis method capable of further improving theeffectiveness of this method in view of practical use.

OBJECT AND SUMMARY OF THE INVENTION

Then, it is a subject of this invention in the present application toprovide a novel technical means for realizing the Mannich type reactionas described above as a solid phase synthesis method and, morespecially, to provide a method of synthesizing pyrazolones by applyingthe Mannich type reaction utilizing the solid phase synthesis.

For attaining the subject described above, a first invention provides aβ-hydrazino ester fixed to a resin represented by the following formula(III):

where P represents a main chain of a resin polymer, Q represents ahydrocarbon side chain optionally having a substituent which may beboned via a heteroatom, R¹, R², R³ and R⁴ each represents a hydrocarbongroup or a heterocyclic group optionally having a substituent.

A second invention provides a production process for a β-hydrazino esterfixed to a resin as defined in the first invention, which comprisesreacting a hydrazone fixed to a resin represented by the followingformula:

P—Q—CO—NH—N═CH—R¹  (II)

where P represents a main chain of a resin, Q represents a hydrocarbonside chain optionally having a substituent which may be boned via aheteroatom and R¹ represents a hydrocarbon group or a heterocyclic groupoptionally having a substituent, with a ketene silyl acetal representedby the following formula:

where R², R³and R⁴ each represents a hydrocarbon group or a heterocyclicgroup which may have a substituent and R⁶ represents a hydrocarbongroup.

Further, a third invention provides a method of synthesizing pyrazoloneswhich comprises reacting a hydrazone fixed to a resin represented by thefollowing formula:

P—Q—CO—NH—N═CH—R¹  (II)

where P represents a main chain of a resin, Q represents a hydrocarbonside chain optionally having a substituent which may be boned via aheteroatom and R¹ represents a hydrocarbon group or a heterocyclic groupoptionally having a substituent, with ketene silyl acetals representedby the following formula:

where R², R³ and R⁴ each represents a hydrocarbon group or aheterocyclic group which may have a substituent respectively and R⁶represents a hydrocarbon group, to synthesize a β-hydrazino ester fixedto a resin represented by the following formula:

where P, Q, R¹, R², R³ and R⁴ have the same meanings as described aboveand then conducting cut out from the solid phase and cyclizing reaction,to synthesize pyrazolones represented by at least one of the followingformulae (A) and (B)

where R¹, R² and R³ have the same meanings as described above.

PREFERRED EMBODIMENTS OF THE INVENTION

The present application provides and a hydrazone fixed to a resin whichcan be derived from a hydrazide fixed to a resin represented by theformula (I) and is represented by a formula (II) as defined in the firstinvention and the second invention described above, which enables solidphase synthesis method by Mannich type reaction and has not been knownat all so far. In any of:

Hydrazide fixed to a resin of the formula  (I)

P—Q—CO—NH—NH₂  (I)

Hydrazone fixed to a resin of the formula  (II)

P—Q—CO—NH—N═CH—R¹  (II),

P represents a main chain of a resin polymer and Q represents a sidechain bonded therewith in which the resin polymer constituting the mainchain P may be an addition polymer, polycondensate, crosslinking productthereof, and, for example, addition polymer of alkenes havingcarbon-carbon doubles bonds or crosslinking polymers therefrom may beconsidered appropriate. Alkenes can include addition polymer or partialcrosslinking product thereof of, for example, aliphatic olefins,aliphatic dienes, as well as α,β-aliphatic unsaturated carboxylic acidsor esters thereof, α,β-aliphatic unsaturated nitriles, aromatic alkenessuch as styrene, α-methylstyrene and divinyl benzene.

Various kinds of polyesters, epoxy resins, polyethers and polyamides aspolycondensates may also be considered.

The side chain Q in this invention may include hydrocarbon chains whichmay have a substituent, or hydrocarbon chains which may have asubstituent where an oxygen atom or nitrogen atom may intervene in thehydrocarbon chain as heteroatom, and the side chain Q may be formedtogether with the main chain: P or may be formed by grafting or pendantaddition after forming the main chain P. In any of cases, thehydrocarbon chain may include various aliphatic groups, cycloaliphaticgroups, aromatic groups and arylaliphatic groups and, for example, therecan be mentioned alkylene chain represent by —(CH₂)_(n)—, a phenylenechain represented by —Ph—, and phenylene alkylene chain represented, forexample, by —Ph—(CH₂)_(n)—, —(CH₂)_(n)—Ph—, —Ph—(CH₂)_(n)—Ph—.Alternatively, there can be also mentioned those bonded via heteroatomsuch as —Ph—O—Ph—, and —Ph—(CH₂)_(n)—O—Ph—.

The hydrocarbons may further contain various kinds of substituents whichare not inhibitive to the solid phase synthesis reaction or furtheractivate the reaction. There can be mentioned those substituents, forexample, hydrocarbon groups such as alkyl group and aryl group, halogenatom, alkoxy group, acyloxy group, alkoxycarbonyl group, nitro group,cyano group and heterocyclic group.

Further, R¹ in the hydrazone fixed to the resin represented by theformula (II) is a hydrocarbon group or a heterocyclic group which mayhave a substituent where the hydrocarbon group may be linear or cyclic,saturated or unsaturated and aliphatic or aromatic, arylaliphatic andthe heterocyclic group may also be various heterocyclic groupscontaining oxygen or nitrogen. Then, there can be mentioned variouskinds of substituents not inhibitive to the solid phase synthesisreaction or further activating the reaction, for example, hydrocarbonssuch as alkyl group or aryl group, halogen atom, alkoxy group, acyloxygroup, alkoxycarbonyl group, nitro group, cyano group and heterocyclicgroup.

The hydrazide fixed to the resin represented by the formula (I) can beproduced by a method, for example, of carboxylating the resin polymerhaving the structure:

P—QH

into a carboxylic acid resin:

P—Q—CO—OH

esterifying the same and then reacting the ester with hydrazine.

The carboxylation is conducted, for example, in accordance with themethod of Frechet, et al by reaction with BuLi and then reacting withCO₂. Of course, carboxylation is not restricted to this method. For theproduction of hydrazide fixed to the resin from the carboxylic acidresin, various modes may also be adopted for the reaction withhydrazide. For example, a carboxylic acid resin is esterified and thenreacted with hydrazine mono-hydrate. The reaction may be conductedwithout using a solvent but use of 1,3-dimethyl-2-imidazolidinone (DMI)as the organic solvent is also effective. In addition, nitrile ornitrogen-containing heterocyclic compound such as pyridine or piperidinemay also be mentioned.

The hydrazine mono-hydrate is used appropriately at a molar ratio ofabout 0.5 to 5 based on the carboxylic acid ester resin. The reactiontemperature is at about 30 to 130° C. and, preferably, at about 60 to110° C.

The hydrazone fixed to the resin of the formula (II) can be obtained byreacting the hydrazide fixed to the resin represented by the formula (I)with aldehydes represented by R¹CHO.

The reaction is conducted appropriately by using a solvent at atemperature of about 10 to 70° C., preferably, about 30 to 60° C. As thesolvent, DMF, DMSO, nitriles, halogenated hydrocarbons or mixed solventthereof with acetic acid may be mentioned as appropriate solvent.

The ratio of the aldehydes to the hydrazide fixed to the resin used forreaction is suitably within a molar ratio of 1 to 10.

The hydrazone fixed to the resin represented by the formula (II) can beused as a substrate for the solid phase Mannich type reaction. Thisreaction is conducted by reacting they hydrazone fixed to the resin ofthe formula (II) with the ketene silyl acetals of the formula (IV).

R²-R⁴ in the formula (III) is a hydrocarbon group or heterocyclic groupwhich may have a substituent and can be selected from the same materialsas R¹ in hydrazine fixed to the resin of the formula (II).

Further, R⁵ may be any of aliphatic, aromatic or arylaliphatichydrocarbon.

The solid phase reaction with the ketene silyl acetals described abovecan be conducted in a solvent by using a rare earth Lewis acid catalyst.The solvent can include, for example, halogenated hydrocarbon, aromatichydrocarbon, ether, nitrile, alcohol and water, or an appropriate mixedsolvent thereof.

The rare earth Lewis acid may be a compound of rare earth metals havingLewis acid property, which may be formed as organic acid ester salt,alcoholate, organic metal compound, organic complex compound and thelike of scandium (Sc) and ytteribium (Yb), yttrium (Y), lanthanum (La),samarium (Sm), neodium (Nd). Among them, rare earth (OTf)₃, for example,Sc(OTf)₃ can be mentioned as more appropriate one.

The ratio of the ketene silyl acetals of the formula (III) to thehydrazone fixed to the resin of the formula (II) is generally from 0.5to 10 molar ratio and, preferably, from 1 to 7 molar. The rare earthLewis acid catalyst is used approximately at a molar ratio generally of0.01 to 1 and, preferably, about 0.1 to 0.6.

The reaction temperature is suitably from −20 to 40° C. and, morepreferably, at or near the room temperature.

The β-hydrazino ester of the formula (III) is obtained by the solidphase reaction described above in this invention.

The β-hydrazino ester provides an important means for constructinglibraries of various kinds of nitrogen-containing organic compounds.

In this invention, pyrazolones represented by either one of the formulae(A) and (B) described above is synthesized by cutting out theβ-hydrazino esters of the formula (III) from the resin and cyclizing thesame.

The reaction can be conducted easily, for example, as a reaction with ametal alcoholate or a base using an alcoholic solvent. The alcoholate orthe base is used, under a heating condition, at a molar ratio generallyfrom 0.8 to 10 and, preferably, from3 to 7 based on the β-hydrazinoester fixed to the resin.

By using various kinds of β-hydrazino esters fixed to the resin,libraries for various kinds of pyrazolones can be synthesized in a solidphase efficiently. The β-hydrazino esters fixed to the resin can beutilized for the synthesis to β-amino acids, β-lactams by cutting outfrom the resin, as well as the pyrazolones are also useful asintermediate products for the synthesis or medicines as physiologicallyactive substances.

This invention will be explained more specifically with reference to thefollowing examples.

EXAMPLES Example 1

In accordance with the following reaction schemes, hydrazide fixed to aresin was formed, which was then reacted with an aldehyde to prepare ahydrazine fixed to the resin, and then pyrazolone was synthesized in asolid phase.

<1> Carboxylic Acid Resin

Under a room temperature, cyclohexane (40 ml) was added topolystyrene/divinyl benzene copolymer (1% crosslinked) (1) (200-400mesh, approx., 5.0 g) manufactured by Aldrich Co., to which were addedN,N,N′,N′-tetramethyl ethylenediamine (4.0 ml, 25 mmol) and n-butyllithium (1.54 M in hexane) (20 ml, 30 mmol). After stirring at 65° C.for 4 hours, the resin was separate by filtration, washed withcyclohexane for three times and a slurrified liquid mixture ofCO₂—tetrahydrofuran was added. Successively, after washing withtetrahydrofuran; 1N hydrochloric acid (1:1) for three times,tetrahydrofuran for three times, water: tetrahydrofuran (1:1) for threetimes, water for three times water: tetrahydrofuran (1:1) for threetimes, tetrahydrofuran for three times and ether for five times, it wasdried at a room temperature under a reduced pressure for 10 hours toobtain a carboxylic acid resin (2) (0.76 mmol/g).

<2> Methyl Ester Resin

Methanol (30 ml) was added to the carboxylic acid resin (2) prepared in(1) above (5.0 g) and after cooled to 0° C., thionyl chloride (8.0 ml,109.6 mmol) and tetrahydrofuran (20 ml) were added. After elevating thetemperature to 60° C. and stirring for 10 hours, the resin was separatedby filtration and washed with methanol for three times, tetrahydrofuranfor three times and ether for five times. When the product was dried ata room temperature under a reduced pressure for 10 hours, a methyl esterresin (3) (0.75 mmol/g) was obtained.

<3> Hydrazide Fixed to a Resin

Hydrazine mono-hydrate (20 ml) was added to the methyl ester resin (2.0g) prepared in (2) above and after stirring at 100° C. for 6 hours, theresin was separated by filtration and washed with water for five times,water: dioxane (1:1) for three times, dioxane for three times and etherfor five times. When the product was dried at a room temperature under areduced pressure for 10 hours, an acyl hydrazine resin (4) (0.75 mmol/g)was obtained.

<4> Hydrazone Fixed to a Resin

N,N-dimethylformamide: acetic acid (20:1, 3.0 ml) was added to the acylhydrazine resin fixed to the resin (4) prepared in <3> above (200.0 mg,0.15 mmol) and, after adding an N,N-dimethylformamide solution (1.0 ml)containing 3-phenyl propion aldehyde (100.6 mg, 0.75 mmol/g), thetemperature was elevated to 50° C. After stirring for 5 hours, the resinwas separated by filtration and washed with N,N-dimethylformamide forthree times, water for three times, tetrahydrofuran for three times andether for five times. When the product was dried at a room temperatureunder a reduced pressure for 10 hours, an acyl hydrazone resin (5) inwhich R^(1═−(CH) ₂)₂Ph (0.69 mmol/g) was obtained.

<5> β-hydrazino Ester Fixed to a Resin

Sc(III) (OTf)₃ (22.1 mg, 0.045 mmol) and methylene chloride (2.0 ml)were added to the acyl hydrazone resin (5) prepared in (4) above and,further, a methylene chloride solution (1.0 ml) containing ketene silylacetal derived from methylisobutylate ester where R², R³, R⁴=Me (131.5mg, 0.75 mmol) was added and stirred at a room temperature for 12 hours.The reaction was terminated by addition of a saturated aqueous solutionof sodium hydrogen carbonate, the resin was separated by filtration and,after washing with methylene chloride for three times, tetrahydrofuranfor three times, water for three times, tetrahydrofuran for three timesand ether for five times, dried at a room temperature under a reducedpressure for 10 hours, β-hydrazino ester resin (6) where R²═−(CH₂)₂Ph,R², R³, R⁴═Me (0.64 mmol/g) was obtained.

<6> Pyrazolone

Methanol (2.0 ml) and sodium methoxide (23.2 mg, 0.43 mmol) were addedto the β-hydrazino ester resin prepared in <5> above (134.0 mg, 0.086mmol) and stirred while heating under reflux for 8 hours. After addingamberlite (IRC-76) the resin was separated by filtration, the solventwas distilled off from the filtrate under a reduced pressure and whenthe residue was purified on thin film silica gel chromatography,pyrazolone (7) represented by the formula (A) where R¹═−(CH₂)₂Ph, R²,R³═Me (14.7 mg, 80%) was obtained.

Example 2

Various kinds of pylazolones were synthesized in the solid phase in thesame procedures as those in Example 1.

The results are shown in Table 1.

TABLE 1 entry R¹ R² R³ R⁴ Yield (A/B) % 1 Ph(CH₂)₂ Me Me Me 80/— 2 C₆H₁₃Me Me Me 88/— 3 (CH₃)₂CHCH₇ Me Me Me 67/— 4 Ph Me Me Me 38/— 5 Ph(CH₂)₂H Me Ph —/38

Example 3

A carboxylic acid resin was produced by conducting Friedel-Craftsreaction using Ph(CH₂)₄COCl to polystyrene and then conducting AlCl₃—LAHreduction followed by carboxylation. By the same subsequent proceduresas those in Example 1, pyrazolones were synthesized in the solid phase.

The results are shown in Table 2.

TABLE 2

Yield (%) entry R¹ R² R³ R⁴ A   /   B 1 Ph(CH₂)₂ Me Me Me 77 (80)⁴ /+ 2Ph(CH₂)₂ Me H Ph −/ 68 (38)⁵ 3 (CH₃)₂CHCH₂ Me H Ph −/ 62 (34)⁴ 4 C₆H₁₅Me H Ph −/ 53 *Non-specer carboxylic resin was used.

Selectivity of pyrazolones (A) and (B) can be changed by changing thefixing resins, particularly, by introducing spacer hydrocarbon chains asshown in Table 2.

Physical properties of the pyrazolones synthesized in Examples 1 to 3above are shown below.

TABLE 3 3-Heptyl-4,4-dimethyl-2-pyrazolin-5-one ¹HNMR δ 0.90(t, 3H,J=6.6Hz). 1.20-1.39(m, 4H), 1.23(s, 6H), 1.63- 1.70(m, 2H), 2.29(t, 2H,J=7.6Hz), 8.35(s, 1H); ¹³CNMR δ 14.0, 20.9, 22.5, 25.2, 27.6, 29.1,31.6, 47.4, 168.6, 181.0 3-(2′-Phenylethyl)-4-methyl-3-pyrazolin-5-one¹HNMR δ 1.25(s, 1H), 1.81(s, 3H), 2.85(brs, 4H), 7.12-7.29(m, 5H);¹³CNMR δ 29.7, 31.0, 33.8, 91.2, 126.5, 128.4, 128.7, 140.1, 140.43-Isobutyl-4-methyl-3-pyrazolin-5-one ¹HNMR δ 0.91(d, 6H, J=6.6Hz),1.26(s, 1H), 1.85-1.92(m, 4H), 2.36(d, 2H, J=6.6Hz), 7.38(brs, 1H);¹³CNMR δ 6.1, 22.1, 28.2 33.9, 96.9, 141.4, 161.23-Heptyl-4-methyl-3-pyrazolin-5-one ¹HNMR δ 0.88(Brs, 3H), 1.25-1.28(m,6H), 1.57(brs, 2H), 1.87(brs, 3H), 2.49(Brs, 2H)

As has been explained specifically above, synthesis of Pyrazolones bythe application of the Mannich type reaction on the solid phasesynthesis is enabled by this invention, and the pyrazolones canefficiently construct libraries.

What is claimed is:
 1. β-hydrazino ester fixed to a resin represented bythe following formula (III):

where P represents a main chain of a resin polymer, Q represents ahydrocarbon side chain optionally having a substituent which may beboned via a heteroatom, R¹, R², R³ and R⁴ each represents a hydrocarbongroup or a heterocyclic group optionally having a substituent.
 2. Aproduction process for a β-hydrazino ester fixed to a resin as definedin claim 3, wherein the process comprises reacting a hydrazone fixed toa resin represented by the following formula: P—Q—CO—NH—N═CH—R¹  (II)where P represents a main chain of a resin, Q represents a hydrocarbonside chain optionally having a substituent which may be boned via aheteroatom and R¹ represents a hydrocarbon group or a heterocyclic groupoptionally having a substituent, with a ketene silyl acetal representedby the following formula:

where R², R³ and R⁴ each represents a hydrocarbon group or aheterocyclic group which may have a substituent and R⁶ represents ahydrocarbon group.
 3. A method of synthesizing pyrazolones whichcomprises reacting a hydrazone fixed to a resin represented by thefollowing formula: P—Q—CO—NH—N═CH—R¹  (II) where P represents a mainchain of a resin, Q represents a hydrocarbon side chain optionallyhaving substituent which may be bonded via a heteroatom and R¹represents a hydrocarbon group or a heterocyclic group optionally havinga substituent, with ketene silyl acetals represented by the followingformula:

where R², R³ and R⁴ each represents a hydrocarbon group or aheterocyclic group which may have a substituent respectively and R⁶represents a hydrocarbon group, to synthesize a β-hydrazino ester fixedto a resin represented by the following formula:

where P, Q, R¹, R², R³ and R⁴ have the same meanings as described above,which is then cut out from the solid phase and put to cyclizingreaction, to synthesize pyrazolones represented by at least one of thefollowing formulae (A), (B)

where R¹, R² and R³ have the same meanings as described above.